ABSTRACT YAP1 has been discovered as a highly potent oncogene that is important for tumorigenesis and metastasis in various cancers. YAP1 is overexpressed in variety of solid tumors either by genetic copy number amplifications or by unknown means. YAP1 is a transcriptional activator that is thought to co-operate with transcription factors and specific chromatin machinery to activate important oncogenic cellular pathways. However, we have limited understanding of which chromatin regulators work synergistically with YAP1 and if they could impart therapeutic vulnerability in YAP1 amplified or overexpressing cancers. In order to better define mechanisms behind's YAP1 oncogenic activity, we purified YAP1 protein complex in ovarian cancer cells, which led to identification of multiple members of Ino80 chromatin remodeling complex. Importantly, UCHL5, a mammalian specific member of Ino80 complex was demonstrated to strongly associate with YAP1. We, and others, have recently shown oncogenic roles for YAP1 in ovarian cancer. Recent studies, including our unpublished studies, have suggested UCHL5 to be a potent oncogenic regulator in variety of cancer types including melanoma, breast cancer, head and neck cancer and ovarian cancer. We further noted that UCHL5 loss diminished YAP1 mediated oncogenic phenotypes in ovarian cells and UCHL5 inhibitor was less active in YAP1 knockdown cells compared to cells with YAP1 high levels. Furthermore, both YAP1 and Ino80 complex are associated with superenhancers loci. Therefore, we hypothesize that Yap1 cooperates with Ino80 complex, or specifically UCHL5 to perform its pro-tumorigenic and pro-metastatic function via regulation of superenhacer function. We further suggest that UCHL5 inhibition may be a viable strategy for therapy in YAP1 amplified cancers. Aim 1: Determine if YAP1 promotes ovarian tumorigenesis through UCHL5. Aim 2: Determine the downstream molecular mechanism of action of co-operativity between YAP1 and UCHL5. Aim 3: Determine whether UCHL5 inhibition could be a viable therapeutic strategy for YAP1 amplified cancers. Impact: Our studies will provide deeper mechanistic understanding of role of YAP1 in modulating chromatin environment on its target genes. Motivated by the concept of precision medicine, proposed study will test whether UCHL5 inhibitors could be a useful therapeutic strategy in YAP1 amplified (or highly expressing) tumors.